Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling

Background: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K‐ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K‐ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway. Methods and Results: Biosynthesis of MBG by cultured human JEG‐3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of MBG in human JEG‐2 cells. Male Sprague‐Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; PPP Conclusions: Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG‐mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy

Сопоставление рентгенологической и патоморфологической картины легких у пациентов с COVID-19

Aim. Compare radiological patterns of COVID-19 pneumonia with pulmonary histology in deceased patients.Materials and methods. The analysis of recent lifetime CT studies of deceased patients was performed with the identification of all existing and leading CT symptoms, including “ground glass”, “crazy paving”, consolidation, as well as the symptom complex (pattern) of organizing pneumonia. Based on the CT symptoms, we selected the target points for taking the specimens by 3-D reconstructions. At the autopsy the lungs were entirely fixed into the front and then marked on CT sections cut from 1 to 3 pieces that were placed in paraffin and processed according to the standard technique, stained with hematoxylin and eosin and fuchsin-facelina. The specimens were analyzed by identifying all available histology changes and selecting the leading one.Results. 45 targeted pieces of lung tissue were obtained from 14 deceased COVID-19 patients (7 men/ 7 women), with an average age of 77.1 ± 12.9 (49–90 years). In deceased patients with the presence of the "ground glass" symptom, in most cases (57.1%) revealed an increase in intra-alveolar cellularity, hyaline membranes, desquamation of the alveolar epithelium and infiltration of the interalveolar septum by lymphocytes, which corresponds to the exudative phase of diffuse alveolar damage (DAP). Mosaic histological changes with alternation of filled alveoli (intraalveolar edema, clusters of red blood cells, macrophages, lymphocytes) and air alveoli were detected from the areas of “crazy paving” zones. Several cases demonstrated interstitial edema and lymphoid infiltration of interalveolar partitions of different severity without their thickening. Areas of consolidation were histologically represented by extensive intraalveolar hemorrhages and / or typical zones of hemorrhagic infarcts in 45.5% of cases. Perilobular consolidation, subpleural cords, symptoms of “halo” and “reverse halo”, which we considered as part of the symptom complex of organizing pneumonia in 43% of cases, morphologically corresponded to organizing pneumonia (the proliferative phase of DAP), as well as to distelectases.Conclusion. Comparison of CT patters and post-mortem pulmonary histology in COVID-19 deceased patients demonstrated that CT symptoms and patterns correspond to certain morphological changes of different phases of DAP.Цель исследования: сопоставить рентгенологические паттерны COVID-19 с гистологическими изменениями у умерших.Материал и методы. Проведен анализ последних прижизненных КТ-исследований умерших пациентов с выделением всех имеющихся и ведущего КТ-симптомов, включая “матовое стекло”, “булыжная мостовая”, консолидация, а также симптомокомплекс (паттерн) организующейся пневмонии. На основании выделенных КТ-симптомов были выбраны прицельные точки взятия материала при помощи построения трехмерных реконструкций. На аутопсии фиксированные целиком легкие разрезались фронтально, далее из обозначенных на компьютерной томограмме участков вырезали от 1 до 3 кусочков, которые заливались в парафин и обрабатывались по общепринятой методике с последующей окраской срезов толщи- ной 3–5 мкм гематоксилином и эозином, пикрофуксин-фукселином. Анализ материала проводили путем выявления всех имеющихся патоморфологических изменений с выделением ведущего из них.Результаты. Были получены 45 прицельно взятых кусочков ткани легкого от 14 умерших (7 мужчин/ 7 женщин), средний возраст 77,1 ± 12,9 (49–90) года. У умерших пациентов с наличием симптома “матово- го стекла” при КТ в большинстве случаев (57,1%) были выявлены увеличение числа клеток в просветах альвеол (внутриальвеолярная клеточность), гиалиновые мембраны, десквамация альвеолярного эпителия и инфильтрация лимфоцитами межальвеолярных перегородок, что может соответствовать признакам экссудативной фазы диффузного альвеолярного повреждения (ДАП). Из участков, обозначенных как зоны “булыжной мостовой”, были выявлены мозаичные гистологические изменения с чередованием заполненных альвеол (внутриальвеолярный отек, скопления эритроцитов, макрофагов, лимфоцитов) и воздушных альвеол, местами при наличии интерстициального отека и лимфоидной инфильтрации межальвеолярных перегородок разной степени выраженности без их утолщения. Участки консолидации гистологически были представлены обширными внутриальвеолярными кровоизлияниями и/или типичными зонами геморрагических инфарктов в 45,5% случаев. Перилобулярная консолидация, субплевральные тяжи, симптомы “ободка” и “обратного ободка”, которые мы расценивали в рамках симптомокомплекса организующейся пневмонии, на компьютерной томограмме в 43% случаев морфологически соответствовали организующейся пневмонии (пролиферативная фаза ДАП), а также дистелектазам.Заключение. При попытке рентгенопатоморфологического сопоставления у пациентов с COVID-19 с поражением легких нами было показано, что различные симптомы и паттерны при КТ соответствуют определенным морфологическим изменениям в различные фазы ДАП

Glycan labeling strategies and their use in identification and quantification

Most methods for the analysis of oligosaccharides from biological sources require a glycan derivatization step: glycans may be derivatized to introduce a chromophore or fluorophore, facilitating detection after chromatographic or electrophoretic separation. Derivatization can also be applied to link charged or hydrophobic groups at the reducing end to enhance glycan separation and mass-spectrometric detection. Moreover, derivatization steps such as permethylation aim at stabilizing sialic acid residues, enhancing mass-spectrometric sensitivity, and supporting detailed structural characterization by (tandem) mass spectrometry. Finally, many glycan labels serve as a linker for oligosaccharide attachment to surfaces or carrier proteins, thereby allowing interaction studies with carbohydrate-binding proteins. In this review, various aspects of glycan labeling, separation, and detection strategies are discussed

BioMAX the first macromolecular crystallography beamline at MAX IV Laboratory

BioMAX is the first macromolecular crystallography beamline at the MAX IV Laboratory 3 GeV storage ring, which is the first operational multi bend achromat storage ring. Due to the low emittance storage ring, BioMAX has a parallel, high intensity X ray beam, even when focused down to 20 mm 5 mm using the bendable focusing mirrors. The beam is tunable in the energy range 5 25 keV using the in vacuum undulator and the horizontally deflecting doublecrystal monochromator. BioMAX is equipped with an MD3 diffractometer, an ISARA high capacity sample changer and an EIGER 16M hybrid pixel detector. Data collection at BioMAX is controlled using the newly developed MXCuBE3 graphical user interface, and sample tracking is handled by ISPyB. The computing infrastructure includes data storage and processing both at MAX IV and the Lund University supercomputing center LUNARC. With state of the art instrumentation, a high degree of automation, a user friendly control system interface and remote operation, BioMAX provides an excellent facility for most macromolecular crystallography experiments. Serial crystallography using either a high viscosity extruder injector or the MD3 as a fixedtarget scanner is already implemented. The serial crystallography activities at MAX IV Laboratory will be further developed at the microfocus beamline MicroMAX, when it comes into operation in 2022. MicroMAX will have a 1 mm x 1 mm beam focus and a flux up to 10 15 photons s 1 with main applications in serial crystallography, room temperature structure determinations and time resolved experiment

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry

Background Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.Methods TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.Results A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 +/- 11.4 years vs. 68.0 +/- 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p< 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p< 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.Conclusion Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.Cardiolog

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry

Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes.Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.Cardiolog

DIHYDROPYRIDINE CALCIUM ANTAGONISTS: THE ROLE IN CURRENT THERAPY OF CARDIO-VASCULAR DISEASES

Classification of calcium antagonists (CA) is presented. Results of the large clinical trials (STONE, STOP-Hypertension-2, ALLHAT, ASCOT-BPLA etc.) devoted to estimation of CA effects on the risk of cardiovascular complications are analyzed. The significant place of dihydropyridine CA in current guidelines on arterial hypertension and ischemic heart disease therapy is underlined. Results of a pilot study on comparison of two amlodipines (original Norvasc and generic Stamlo M) are discussed

THE CHOICE OF NITRATE THERAPY IN PATIENTS WITH STABLE ANGINA: COMPARATIVE STUDY OF ISOSORBIDE DINITRATE (IN USUAL TABLETS) WITH ISOSORBIDE-5-MONONITRATE (IN VARIOUS PRESENTATIONS)

Aim. To study efficacy and tolerability of isosorbide-5-mononitrate (IMN) in various presentations in comparison with isosorbide dinitrate (IDN) in usual tablets in patients with stable angina.Material and Methods. 22 patients (5 women and 17 men) with stable angina of II-III functional class were involved into open randomized comparative crossover study. Patients were split in 3 groups and received each of studied drugs during 4 weeks. IDN (Nitrosorbide, Nizpharm, Russia) in usual tablets 10 mg prescribed for 3 times a day administration; IMN (Monocinque,Berlin-Chemie, German) in tablets 20 mg prescribed for 2 times a day administration. After 1 week therapy the doses of IDN or IMN doubled if it was clinically necessary. Retarded presentation of IMN (Monocinque Retard, Berlin-Chemie, German) in capsules 50 mg prescribed once daily. Drug efficacy was evaluated by changes in clinical symptoms, number of angina attacks, demand in short-acting sublingual nitroglycerin as well as physical activity tolerance.Results. After 4 weeks 18 patients completed study, 2 patients dropped out because of protocol nonobservance and 2 patients dropped out because of side effects (headache). IDN therapy in adjusted dose provided antianginal effect in 15 (83,3%) patients: a number of angina attacks decreased in 39,6%, short-acting nitroglycerin demand reduced in 47,7%. Monocinque in adjusted dose provided antianginal effect in 16 (88,9%) patients: a number of angina attacks decreased in 60%, short-acting nitroglycerin demand reduced in 63%. Monocinque Retard provided good antianginal effect in 18 (100%) patients: a number of angina attacks decreased in 72%, short-acting nitroglycerin demand reduced in 84,8%. There were not significant differences in frequency and severity of headache between studied drugs.Conclusion. IMN therapy with both presentations (administrated 1 or 2 times a day) was more convenient and effective than IDN (administrated 3 times a day)

COMPARATIVE EVALUATION OF EFFICACY AND TOLERABILITY OF ORIGINAL AND GENERIC BISOPROLOL IN PATIENTS WITH ARTERIAL HYPERTENSION 1-2 GRADE

Aim. To study a clinical equivalence of two medications of bisoprolol in patients with arterial hypertension (AH) 1-2 grades.Methods. Efficacy and tolerability of original (Concor, NYCOMED, Merck KGaA) and generic (Bisogamma, WORWAG PHARMA GmbH &amp; Co) bisoprolol were investigated in open-label cross-over randomized comparative study. 32 patients (15 males and 17 females) with AH of 1 (66%) and 2 (34%) grades aged of 60 y.o. on average were involved. After 2 weeks of wash-out period original or generic bisoprolol 5 mg daily was prescribed. If necessary a dose of drug was doubled in two weeks. In patients with significant bradycardia (heart rate &lt;55 bp/min) or atrioventricular block (1-2 degree) hydrochlorothiazide (HCT) 12.5-25 mg per day was added. There was another 2-week wash-out period between two active treatment periods.Results. Systolic and diastolic blood pressure (SBP, DBP) as well as heart rate (HR) were decreased significantly after two weeks of treatment with original bisoprolol (∆SBP=13.8±8.9, ∆DBP=8.5±8.6 mmHg and ∆HR=9.9±13.7 bp/min). Generic medication also significantly reduced SBP, DBP and HR (∆SBP=10.1±10.3, ∆DBP=7.1±7.2 mmHg and ∆HR=9.3±9.4 bp/min). Target SBP/DBP levels were achieved in 62.5%/71.9% of patients in Concor group and in 43.7%/62.5% of patients in Bisogamma group. There was a tendency to additional SBP decrease in patients treated with bisoprolol at a dose of 10 mg and with HCT in Concor group (–5.1±7.4 mmHg; p&lt;0.09) and in Bisogamma group (–5.2±7.9 mmHg; p&lt;0.06). After 4 weeks of treatment target SBP/DBP levels were achieved in 90.1%/96.9% of patients in Concor group and 75%/84.4% patients in Bisogamma group. The investigated parameters did not change significantly in a period between the 4 and 6 weeks of treatment. Monotherapy with Concor and Bisogamma was effective in 84.4% in 62% of patients, respectively (p&lt;0.05). After 6 weeks of treatment target SBP and DBP levels were achieved in 96.9% of patients in the both groups. Average daily doses of original and generic bisoprolol were 6.5 and 7.2 mg, respectively.Conclusion. Generic bisoprolol demonstrated lower antihypertensive efficacy and similar tolerability in comparison with original bisoprolol. </p

COMPARATIVE EVALUATION OF EFFICACY AND TOLERABILITY OF ORIGINAL AND GENERIC BISOPROLOL IN PATIENTS WITH ARTERIAL HYPERTENSION 1-2 GRADE

Aim. To study a clinical equivalence of two medications of bisoprolol in patients with arterial hypertension (AH) 1-2 grades.Methods. Efficacy and tolerability of original (Concor, NYCOMED, Merck KGaA) and generic (Bisogamma, WORWAG PHARMA GmbH &amp; Co) bisoprolol were investigated in open-label cross-over randomized comparative study. 32 patients (15 males and 17 females) with AH of 1 (66%) and 2 (34%) grades aged of 60 y.o. on average were involved. After 2 weeks of wash-out period original or generic bisoprolol 5 mg daily was prescribed. If necessary a dose of drug was doubled in two weeks. In patients with significant bradycardia (heart rate &lt;55 bp/min) or atrioventricular block (1-2 degree) hydrochlorothiazide (HCT) 12.5-25 mg per day was added. There was another 2-week wash-out period between two active treatment periods.Results. Systolic and diastolic blood pressure (SBP, DBP) as well as heart rate (HR) were decreased significantly after two weeks of treatment with original bisoprolol (∆SBP=13.8±8.9, ∆DBP=8.5±8.6 mmHg and ∆HR=9.9±13.7 bp/min). Generic medication also significantly reduced SBP, DBP and HR (∆SBP=10.1±10.3, ∆DBP=7.1±7.2 mmHg and ∆HR=9.3±9.4 bp/min). Target SBP/DBP levels were achieved in 62.5%/71.9% of patients in Concor group and in 43.7%/62.5% of patients in Bisogamma group. There was a tendency to additional SBP decrease in patients treated with bisoprolol at a dose of 10 mg and with HCT in Concor group (–5.1±7.4 mmHg; p&lt;0.09) and in Bisogamma group (–5.2±7.9 mmHg; p&lt;0.06). After 4 weeks of treatment target SBP/DBP levels were achieved in 90.1%/96.9% of patients in Concor group and 75%/84.4% patients in Bisogamma group. The investigated parameters did not change significantly in a period between the 4 and 6 weeks of treatment. Monotherapy with Concor and Bisogamma was effective in 84.4% in 62% of patients, respectively (p&lt;0.05). After 6 weeks of treatment target SBP and DBP levels were achieved in 96.9% of patients in the both groups. Average daily doses of original and generic bisoprolol were 6.5 and 7.2 mg, respectively.Conclusion. Generic bisoprolol demonstrated lower antihypertensive efficacy and similar tolerability in comparison with original bisoprolol